The mechanism of cytotoxicity of 4‐nonylphenol in a human hepatic cell line involves ER‐stress, apoptosis, and mitochondrial dysfunction

Abstract

4-Nonylphenol (4-NP) is an emerging environmental pollutant widely diffused in waters and sediments. It mainly derives from the degradation of alkyl phenol ethoxylates, compounds commonly employed as industrial surfactants. 4-NP strongly contaminates foods and waters for human use; thus, it displays a wide range of toxic effects not only for aquatic organisms but also for mammals and humans. After ingestion through the diet, it tends to accumulate in body fluids and tissues. One of the main organs where 4-NP and its metabolites are concentrated is the liver, where it causes, even at low doses, oxidative stress and apoptosis. In the present study, we analyzed the effects of 4-NP on a human hepatic cell line (HepG2) to deepen the knowledge of its cytotoxic mechanism. We found that 4-NP, in a range of concentration from 50 to 100 μM, significantly reduced cell viability; it caused a partial block of proliferation and induced apoptosis with activation of caspase-3 and overexpression of p53. Moreover, 4-NP induced-apoptosis seemed to involve both an ER-stress response, with the appearance of high level of GRP78, CHOP and the spliced XBP1, and a dysregulation of mitochondrial physiology, characterized by an overexpression of main markers of mitochondrial dynamics. Our data support the idea that a daily consumption of 4-NP-contaminated foods may lead to local damages at the level of gastrointestinal system, including liver, with negative consequences for the organ physiology.

Peculiar Ca2+ Homeostasis, ER Stress, Autophagy, and TG2 Modulation in Celiac Disease Patient-Derived Cells

“…To quantify TG2, GRP78 and CHOP mRNA levels after treatments with THP for 4 h and 24 h, real-time PCR analyses were performed according to protocols previously reported [ 20 , 37 , 38 ]. For each cell culture, at least two independent experiments were performed.…”

“…For each cell culture, at least two independent experiments were performed. To evaluate the unspliced and the spliced form for the XBP1 transcript, after treatments with THP for 4 h, a conventional RT-PCR was performed as previously reported [ 37 , 38 , 39 ], followed by the visualization of the obtained cDNA in a 2.5% agarose gel stained with ethidium bromide.…”

Endocrine-Disrupting Chemicals and Their Adverse Effects on the Endoplasmic Reticulum

“…Regarding the influence of 4NP, studies detected CHOP upregulation in rat primary cortical neurons [71], human liver HepG2 cells [72], and PC12 cells [73]. Moreover, GRP78 is upregulated in every reference [70][71][72][73][74][75]. Several disease models have been reported.…”

“…In addition to the intestine, the liver is the main site for detoxification. Paolella et al examined the cytotoxicity of 4NP to human liver cells [72]. The cell viability of the hepatoma cell line, the HepG2 cells, decreased after 4NP treatment.…”

Protective Role of Hsp27 in the Nonylphenol-Induced Locomotory and Longevity Toxicity

“…3,4 Living organisms are exposed to nonylphenol throughout their lives via the ingestion of contaminated food/water, causing a disturbance in hormonal balance and consequently leading to various health disorders such as behavior disorders, developmental and reproductive abnormalities, and alterations in immune functions. [5][6][7] In a study by Paolella et al, 8 nonylphenol exposure causes ER stress, apoptosis, and mitochondrial dysfunction in the hepatic cell line. Additionally, it was noted that nonylphenol elicits oxidative stress in a dose-and concentration dependent manner.…”